In the Siberian kindred of segregating autosomal dominant cerebellar ataxia, 131 patients were characterized clinically and 2 pathologically. The collected pedigrees include 1235 individuals, of which 360 are at a 50% risk and 242 at a 25% risk of having the disease. Ataxia in this kindred has been genetically linked to the SCA1 gene on chromosome 6p and the pedigree screened for the recently described CAG repeat expansion in this gene using GeneScan program (ABI). The normal allele had 20 to 37 repeat units and a CAT or CATCAGCAT interruption between the first and the second sequences of 10 to 17 CAG repeats. The pathogenic allele was extended to 39 to 60 uninterrupted repeats in all 59 analyzed ataxia patients. The number of repeat units correlated inversely with the age of disease onset. Repeat numbers of 43 to 55 were also found in 39 of 105 tested unaffected first and second degree relatives. Homozygosity for the elongated allele was observed in two affected individuals and an unaffected child; the age of onset and clinical course were no different from the heterozygotes carrying alleles with a similar number of repeat units. Testing for the SCA1 gene mutation has been performed in 44 American families with ataxia; only two were shown to have a CAG triplet expansion. Genetic typing of a large family from Virginia indicated chromosome 14q as a probable gene location. Further attempts to identify mutations in American ataxia families are underway. Another large Virginian family tracing its ancestry to Colonial America and a family from Texas expressing essential tremor and focal dystonia are under genetic linkage study with the use of highly polymorphic minisatellite markers. The size and uniform clinical expression make these families uniquely suitable for genetic identification.